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Cited by 661Sarcoma Diagnosis and TreatmentBone Tumor Diagnosis and TreatmentsCardiac tumors and thrombi

Osteosarcoma

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Beird, Hannah C., Bielack, Stefan S., Flanagan, Adrienne M., Gill, Jonathan, Heymann, Dominique, Janeway, Katherine A., Livingston, J. Andrew, Roberts, Ryan D. +2 more·2022·Nature Reviews Disease Primers
DOI 10.1038/s41572-022-00409-y
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Abstract

Osteosarcoma is the most common primary malignant tumour of the bone. Osteosarcoma incidence is bimodal, peaking at 18 and 60 years of age, and is slightly more common in males. The key pathophysiological mechanism involves several possible genetic drivers of disease linked to bone formation, causing malignant progression and metastasis. While there have been significant improvements in the outcome of patients with localized disease, with event-free survival outcomes exceeding 60%, in patients with metastatic disease, event-free survival outcomes remain poor at less than 30%. The suspicion of osteosarcoma based on radiographs still requires pathological evaluation of a bone biopsy specimen for definitive diagnosis and CT imaging of the chest should be performed to identify lung nodules. So far, population-based screening and surveillance strategies have not been implemented due to the rarity of osteosarcoma and the lack of reliable markers. Current screening focuses only on groups at high risk such as patients with genetic cancer predisposition syndromes. Management of osteosarcoma requires a multidisciplinary team of paediatric and medical oncologists, orthopaedic and general surgeons, pathologists, radiologists and specialist nurses. Survivors of osteosarcoma require specialized medical follow-up, as curative treatment consisting of chemotherapy and surgery has long-term adverse effects, which also affect the quality of life of patients. The development of osteosarcoma model systems and related research as well as the evaluation of new treatment approaches are ongoing to improve disease outcomes, especially for patients with metastases. Osteosarcoma is the most common primary malignant tumour of the bone. This Primer by Gorlick and colleagues summarizes the epidemiology, mechanisms, diagnosis and treatment of this disorder as well as the quality of life of patients and open research questions.

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Crossref · 10.1038/s41572-022-00409-y

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  • Findingcitation

    In EURAMOS-1, patients randomized and not randomized to salvage therapy had event-free survival rates of 53% (95% CI 47-53%) and 55% (95% CI 49-60%), respectively.

    “Patients who were and were not randomized to such salvage therapy had event-free survival rates of 53% (95% CI 47-53%) and 55% (95% CI 49-60%), respectively.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [114] Marina, N. M. et al. Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial. Lancet Oncol. 17, 1396–1408 (2016). An international randomized clinical trial fails to show benefit of addition of I/E to MAP chemotherapy in the primary treatment of osteosarcoma. source

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  • Premisecitation

    Cancer predisposition syndromes considered risk factors for osteosarcoma include Li-Fraumeni syndrome, hereditary retinoblastoma, Diamond-Blackfan anaemia, and RECQ-family DNA helicase disorders such as Rothmund-Thomson, RAPADILINO, Bloom and Werner syndromes.

    “A growing number of cancer predisposition syndromes are considered risk factors for the development of osteosarcoma, including Li-Fraumeni syndrome, hereditary retinoblastoma and Diamond-Blackfan anaemia as well as primary DNA helicase disorders involving the RECQ family of genes, including Rothmund-Thomson syndrome, RAPADILINO syndrome, Bloom syndrome and Werner syndrome 19,20,21”
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    • cites [19] Vlachos, A., Rosenberg, P. S., Atsidaftos, E., Alter, B. P. & Lipton, J. M. Incidence of neoplasia in Diamond Blackfan anemia: a report from the Diamond Blackfan Anemia Registry. Blood 119, 3815–3819 (2012). source

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    • cites [20] Wang, L. L. et al. Association between osteosarcoma and deleterious mutations in the RECQL4 gene in Rothmund-Thomson syndrome. J. Natl Cancer Inst. 95, 669–674 (2003). source

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    • cites [21] Lu, L., Jin, W. & Wang, L. L. RECQ DNA helicases and osteosarcoma. Adv. Exp. Med. Biol. 1258, 37–54 (2020). source

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  • Premisecitation

    Patients with radiographically confirmed non-metastatic osteosarcoma have a 5-year event-free survival of approximately 60%.

    “Those patients with radiographically confirmed non-metastatic osteosarcoma have a 5-year event-free survival of ~60% 9 .”
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    • cites [9] Gill, J. & Gorlick, R. Advancing therapy for osteosarcoma. Nat. Rev. Clin. Oncol. 18, 609–624 (2021). source

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  • Premisecitation

    Osteosarcoma in adults over 40 years and elderly over 60 years tends to occur secondary to other conditions such as Paget disease, transformation of benign bone conditions, or late effects of therapeutic irradiation.

    “Osteosarcoma in adults (age >40 years) and elderly populations (age >60 years) tends to occur secondary to other conditions, such as Paget disease of bone, as transformation of other benign bone conditions or as a late effect of therapeutic irradiation 14 .”
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    • cites [14] Czerniak, B. Dorfman and Czerniak’s Bone Tumors E-Book (Elsevier Health Sciences, 2015).

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  • Premisecitation

    Exposure to alkylating chemotherapy, particularly when given with radiotherapy, is associated with an increased incidence of subsequent osteosarcoma in childhood cancer survivors.

    “Similarly, exposure to alkylating chemotherapy, particularly when given along with radiotherapy, has been associated with an increased incidence of subsequent osteosarcoma in childhood cancer survivors 25 .”
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    • cites [25] Tucker, M. A. et al. Bone sarcomas linked to radiotherapy and chemotherapy in children. N. Engl. J. Med. 317, 588–593 (1987). source

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    Findingcitation

    The recommended staging work-up reveals lung metastases in 15-20% of patients and occasionally identifies tumours in other bones or, rarely, other sites.

    “This work-up recommendation reveals lung metastases in 15-20% of patients, and occasionally identifies tumours within other bones or, very rarely, lesions at other sites.”
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    • cites [107] Meyer, J. S. et al. Imaging guidelines for children with Ewing sarcoma and osteosarcoma: a report from the Children’s Oncology Group Bone Tumor Committee. Pediatr. Blood Cancer 51, 163–170 (2008). source

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    Findingcitation

    In trials for relapsed/refractory osteosarcoma, MTKIs were effective in reducing PFS and became mainstay.

    “In these trials, MTKIs were effective in reducing PFS, becoming the mainstay of treatments for patients with relapsed disease.”
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    • cites [12] Mirabello, L. et al. Frequency of pathogenic germline variants in cancer-susceptibility genes in patients with osteosarcoma. JAMA Oncol. 6, 724–734 (2020). This study demonstrates a high frequency of potentially pathogenic germline mutations in patients with osteosarcoma, supporting the role of germline genetic testing. source

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    • cites [159] Boddu, P. et al. Treated secondary acute myeloid leukemia: a distinct high-risk subset of AML with adverse prognosis. Blood Adv. 1, 1312–1323 (2017). source

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    • cites [160] Armstrong, G. T. et al. Late mortality among 5-year survivors of childhood cancer: a summary from the childhood cancer survivor study. J. Clin. Oncol. 27, 2328–2338 (2009). source

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    Premisecitation

    Osteosarcoma is the most common primary malignant tumour of bone.

    “Osteosarcoma is the most common primary malignant tumour of the bone.”
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    • cites [1] Mirabello, L., Troisi, R. J. & Savage, S. A. Osteosarcoma incidence and survival rates from 1973 to 2004: data from the surveillance, epidemiology, and end results program. Cancer 115, 1531–1543 (2009). source

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    Premisecitation

    Osteosarcoma incidence is bimodal, with peaks around 18 and 60 years of age.

    “Osteosarcoma incidence is bimodal, peaking at 18 and 60 years of age”
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    • cites [1] Mirabello, L., Troisi, R. J. & Savage, S. A. Osteosarcoma incidence and survival rates from 1973 to 2004: data from the surveillance, epidemiology, and end results program. Cancer 115, 1531–1543 (2009). source

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    Premisecitation

    Osteosarcoma is histologically defined as a tumour of osteoid-producing cells that often exist within an admixture of adipogenic, muscle, spindle, fibroblastic and chondroblastic cells.

    “Osteosarcoma is defined histologically as a tumour of osteoid-producing cells, which often exist within an admixture of adipogenic, muscle, spindle, fibroblastic and chondroblastic cells 3 .”
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    • cites [3] Klein, M. J. & Siegal, G. P. Osteosarcoma: anatomic and histologic variants. Am. J. Clin. Pathol. 125, 555–581 (2006). source

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    Premisecitation

    In children and adolescents, osteosarcoma incidence is approximately 3-4.5 cases per million population per year.

    “with an incidence in children and adolescents of ~3-4.5 cases per million population per year 10 .”
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    • cites [10] Mirabello, L., Troisi, R. J. & Savage, S. A. International osteosarcoma incidence patterns in children and adolescents, middle ages and elderly persons. Int. J. Cancer 125, 229–234 (2009). source

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    Premisecitation

    Health disparities do not seem to have a major effect on osteosarcoma survival outcomes, but data are limited.

    “Health disparities do not seem to have a major effect on survival outcomes but data are limited 17 .”
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    • cites [17] Ilcisin, L. A. S. et al. Poverty, race, ethnicity, and survival among U.S. children with non-metastatic osteosarcoma treated on EURAMOS-1: a report from the Children’s Oncology Group. J. Clin. Oncol. 40, 10004 (2022). source

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    Premisecitation

    Osteosarcoma is particularly uncommon in children younger than 10 years, in whom the genetic aetiology may differ from that in adolescents.

    “It is particularly uncommon in young children <10 years of age in whom the genetic aetiology may be different to that in adolescents 12 .”
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    • cites [12] Mirabello, L. et al. Frequency of pathogenic germline variants in cancer-susceptibility genes in patients with osteosarcoma. JAMA Oncol. 6, 724–734 (2020). This study demonstrates a high frequency of potentially pathogenic germline mutations in patients with osteosarcoma, supporting the role of germline genetic testing. source

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    Interpretationcitation

    Polygenic interactions may explain the association between tall stature and risk of osteosarcoma.

    “In addition, polygenic interactions may explain the association between tall stature and risk of osteosarcoma 24 .”
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    • cites [24] Mirabello, L. et al. Height at diagnosis and birth-weight as risk factors for osteosarcoma. Cancer Causes Control 22, 899–908 (2011). source

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    Interpretationcitation

    Genomic complexity in osteosarcoma has long been interpreted as a sign of chromosomal instability, but emerging data suggest that the mechanisms triggering complexity are active early in malignant transformation.

    “This genomic complexity has long been interpreted as a sign of chromosomal instability but emerging data suggest that the mechanisms triggering complexity are active early in the process of malignant transformation 35,37 .”
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    • cites [35] Sayles, L. C. et al. Genome-informed targeted therapy for osteosarcoma. Cancer Discov. 9, 46–63 (2019). A study that defines potentially actionable molecular subtypes of osteosarcoma. source

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    • cites [37] Rajan, S. et al. Remarkably stable copy-number profiles in osteosarcoma revealed using single-cell DNA sequencing. Preprint at bioRxiv https://doi.org/10.1101/2021.08.30.458268 (2021). source

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    Premisecitation

    These rearrangements give rise to genome-wide copy number alterations usually dominated by copy number loss, including of PTEN and CDKN2A/B, but with recurrent amplifications of MYC, VEGFA and CCNE1.

    “These rearrangements give rise to genome-wide copy number alterations, usually dominated by copy number loss, including of PTEN and CDKN2A/B, but with recurrent amplifications of MYC, VEGFA and CCNE1 (ref.35 ).”
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    • cites [35] Sayles, L. C. et al. Genome-informed targeted therapy for osteosarcoma. Cancer Discov. 9, 46–63 (2019). A study that defines potentially actionable molecular subtypes of osteosarcoma. source

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    Premisecitation

    The genomic landscape of osteosarcoma tumours is usually dominated by widespread structural rearrangements, suggesting that several mutational mechanisms, including chromothripsis, chromoplexy, kataegis and other structure-altering mechanisms, are involved.

    “The genomic landscape of osteosarcoma tumours is usually dominated by widespread structural rearrangements, suggesting that several different mutational mechanisms, including chromothripsis, chromoplexy, kataegis and other structure-altering mechanisms, are involved 32,33,34 .”
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    • cites [32] Cortés-Ciriano, I. et al. Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing. Nat. Genet. 52, 331–341 (2020). source

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    • cites [33] Chen, X. et al. Recurrent somatic structural variations contribute to tumorigenesis in pediatric osteosarcoma. Cell Rep. 7, 104–112 (2014). The majority of TP53 loss in osteosarcoma occurs through intron 1 rearrangements or deletions rather than through point mutations. source

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    • cites [34] Perry, J. A. et al. Complementary genomic approaches highlight the PI3K/mTOR pathway as a common vulnerability in osteosarcoma. Proc. Natl Acad. Sci. USA 111, E5564–E5573 (2014). source

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    Premisecitation

    Radiotherapy-associated osteosarcomas tend to occur within the radiation field after a latency period of more than 10 years and are more frequent in patients with cancer predisposition syndromes such as Li-Fraumeni syndrome or hereditary retinoblastoma.

    “Radiotherapy-associated osteosarcomas tend to occur within the radiation field following a long latency period of >10 years and are more frequent in patients with cancer predisposition syndromes such as Li-Fraumeni syndrome or hereditary retinoblastoma 25 .”
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    • cites [25] Tucker, M. A. et al. Bone sarcomas linked to radiotherapy and chemotherapy in children. N. Engl. J. Med. 317, 588–593 (1987). source

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    Premisecitation

    Malignant transformation to osteosarcoma is estimated to occur in about 1% of patients with Paget disease.

    “it is estimated that malignant transformation to osteosarcoma occurs in ~1% of patients with Paget disease 26 .”
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    • cites [26] Cundy, T. Paget’s disease of bone. Metabolism 80, 5–14 (2018). source

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    Interpretationcitation

    Osteosarcoma tumours often show signs of whole-genome duplication, which probably occurs in response to stresses imposed by pervasive copy number losses.

    “Osteosarcoma tumours often show signs of whole-genome duplication, which probably occurs in response to stresses imposed by pervasive copy number losses 36 .”
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    • cites [36] Wu, C. C. et al. Immuno-genomic landscape of osteosarcoma. Nat. Commun. 11, 1008 (2020). Molecular profiling of samples from patients with osteosarcoma characterizes immune subsets, including immune enrichment among older patients. source

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    Premisecitation

    SEER data show age-adjusted osteosarcoma incidence rates of 1.9 per million for ages 0-9, 6.7 per million for ages 10-24, 1.9 per million for ages 25-59, and 2 per million for ages 60 and older.

    “The age-adjusted incidence rate was 1.9 per million for those aged 0-9 years, 6.7 per million for those aged 10-24 years, 1.9 per million for those aged 25-59 years and 2 per million for those aged ≥60 years.”
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    • cites [16] Cole, S., Gianferante, D. M., Zhu, B. & Mirabello, L. Osteosarcoma: a surveillance, epidemiology, and end results program‐based analysis from 1975 to 2017. Cancer 128, 2107–2118 (2022). source

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    Premisecitation

    Osteosarcoma is slightly more common in males, with an average male-to-female ratio of 1.4:1.

    “Osteosarcoma is slightly more common in males, with an average male-to-female ratio of 1.4:1 (ref.15 ).”
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    • cites [15] Brown, H. K., Schiavone, K., Gouin, F., Heymann, M.-F. & Heymann, D. Biology of bone sarcomas and new therapeutic developments. Calcif. Tissue Int. 102, 174–195 (2018). source

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    Premisecitation

    In the USA, osteosarcoma accounts for less than 1% of all new cancer diagnoses, with about 1,000 new cases per year, half occurring in children and adolescents.

    “In the USA, osteosarcoma accounts for <1% of all new cancer diagnoses with ~1,000 new cases diagnosed per year, half of these cases occurring in children and adolescents 1 .”
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    • cites [1] Mirabello, L., Troisi, R. J. & Savage, S. A. Osteosarcoma incidence and survival rates from 1973 to 2004: data from the surveillance, epidemiology, and end results program. Cancer 115, 1531–1543 (2009). source

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    Premisecitation

    The rise and peak in osteosarcoma incidence in adolescents up to age 24 is often attributed to hormonal changes during puberty, with an earlier peak in girls than in boys.

    “The incidence rise and peak in adolescents up to the age of 24 years are often attributed to the hormonal changes that occur during puberty with an earlier peak in girls than in boys 13 .”
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    • cites [13] Glass, A. G. & Fraumeni, J. F. Jr. Epidemiology of bone cancer in children. J. Natl Cancer Inst. 44, 187–199 (1970).

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    Interpretationcitation

    Epidemiological observations support the interpretation that osteosarcoma arises most frequently within the metaphyses of long bones during peak linear growth, suggesting that rapidly proliferating bone-producing and cartilage-producing cells are susceptible to transformation.

    “Epidemiological observations support this interpretation as tumours were found to arise most frequently within the metaphyses of long bones in children, adolescents and young adults during times of peak linear growth, suggesting that the bone-producing and cartilage-producing cells that proliferate rapidly during those growth spurts are those susceptible to the transformation giving rise to osteos”
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    • cites [29] Jones, K. B. Osteosarcomagenesis: modeling cancer initiation in the mouse. Sarcoma 2011, 694136 (2011). source

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    • cites [30] Mutsaers, A. J. & Walkley, C. R. Cells of origin in osteosarcoma: mesenchymal stem cells or osteoblast committed cells? Bone 62, 56–63 (2014). source

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    Premisecitation

    Whether benign bone tumours trigger osteosarcoma transformation through accumulation of genetic and epigenetic events or through creation of a permissive environment remains unclear.

    “Whether these benign bone tumours trigger a transformation based on the accumulation of genetic and epigenetic events or the creation of an environment permissive to malignant transformation remains unclear 28 .”
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    • cites [28] Picci, P. et al. Late sarcoma development after curettage and bone grafting of benign bone tumors. Eur. J. Radiol. 77, 19–25 (2011). source

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    Premisenone given

    In patients with metastatic osteosarcoma, event-free survival remains less than 30%.

    “in patients with metastatic disease, event-free survival outcomes remain poor at less than 30%.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Osteosarcoma incidence in children and adolescents increased from the 1970s to the 2000s but declined in adults over 60 years of age.

    “Notably, the incidence of osteosarcoma in children and adolescents has increased from the 1970s to the 2000s but has declined in adults >60 years of age.”
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    • cites [16] Cole, S., Gianferante, D. M., Zhu, B. & Mirabello, L. Osteosarcoma: a surveillance, epidemiology, and end results program‐based analysis from 1975 to 2017. Cancer 128, 2107–2118 (2022). source

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    Interpretationcitation

    In older adults, osteosarcomas may arise in the setting of Paget disease and other bone disorders, suggesting a role of abnormal bone turnover in osteosarcoma pathogenesis.

    “Particularly in older adults, osteosarcomas may also arise in the setting of Paget disease of bone and other bone disorders, suggesting a role of abnormal bone turnover in osteosarcoma pathogenesis 26 .”
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    • cites [26] Cundy, T. Paget’s disease of bone. Metabolism 80, 5–14 (2018). source

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    Premisecitation

    The frequency of germline mutations in patients with osteosarcoma ranges from 18% to 28%, and these mutations are more common in younger patients.

    “The frequency of germline mutations in patients with osteosarcoma ranges from 18% to 28% and these mutations are more common in younger patients 12,18 .”
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    • cites [12] Mirabello, L. et al. Frequency of pathogenic germline variants in cancer-susceptibility genes in patients with osteosarcoma. JAMA Oncol. 6, 724–734 (2020). This study demonstrates a high frequency of potentially pathogenic germline mutations in patients with osteosarcoma, supporting the role of germline genetic testing. source

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    • cites [18] Zhang, J. et al. Germline mutations in predisposition genes in pediatric cancer. N. Engl. J. Med. 373, 2336–2346 (2015). source

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    Premisecitation

    Osteosarcoma incidence has a primary peak in adolescents and young adults and a second smaller peak in the seventh and eighth decades of life.

    “Osteosarcoma incidence has a bimodal age distribution with a primary peak in adolescents and young adults and a second, smaller peak in the seventh and eighth decade of life 1”
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    • cites [1] Mirabello, L., Troisi, R. J. & Savage, S. A. Osteosarcoma incidence and survival rates from 1973 to 2004: data from the surveillance, epidemiology, and end results program. Cancer 115, 1531–1543 (2009). source

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    Premisecitation

    Patients with retinoblastoma and Rothmund-Thomson syndrome might present with osteosarcoma in their teens, whereas osteosarcoma associated with Werner syndrome or Li-Fraumeni syndrome presents in middle age.

    “Patients with retinoblastoma and Rothmund-Thomson syndrome might present with osteosarcoma in their teens, and osteosarcoma associated with Werner syndrome or Li-Fraumeni syndrome presents in middle age 22,23 .”
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    • cites [22] Hameed, M. & Mandelker, D. Tumor syndromes predisposing to osteosarcoma. Adv. Anat. Pathol. 25, 217–222 (2018). source

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    • cites [23] Calvert, G. T. et al. At-risk populations for osteosarcoma: the syndromes and beyond. Sarcoma 2012, 152382 (2012). source

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    Premisereasoning

    A major caveat of precision strategies in osteosarcoma is that each alteration applies to only a very limited number of patients, making clinical trials of these subgroups challenging, and many more common alterations are not associated with targetable therapies.

    “A major caveat is that each of these alterations only applies to a very limited number of patients, making clinical trials of these subgroups challenging, and many more common alterations are not associated with targetable therapies.”
    Quote in the paperSubstantial claim

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    Interpretationcitation

    Osteosarcoma development can be described by the conjunction of oncogenic events initiating malignant transformation, progressive increase of genetic aberrations with increasing proliferation of cells committed to the osteoblast lineage during bone growth, and involvement of a permissive microenvironment that is a prerequisite for cancer cell growth.

    “Osteosarcoma development can be described by the conjunction of multiple factors: oncogenic events that initiate malignant transformation, a progressive increase of genetic aberrations with the increasing proliferation rate of cells committed towards the osteoblast lineage during bone growth 44 , and involvement of a permissive microenvironment, which is a prerequisite for the growth of cancer”
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    • cites [44] Kovac, M. et al. Exome sequencing of osteosarcoma reveals mutation signatures reminiscent of BRCA deficiency. Nat. Commun. 6, 8940 (2015). source

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    Premisecitation

    Deletion of ATRX seems to activate alternative lengthening of telomeres and is associated with decreased survival in osteosarcoma.

    “deletion of ATRX, which seems to activate alternative lengthening of telomeres and is associated with decreased survival 36,43 .”
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    • cites [36] Wu, C. C. et al. Immuno-genomic landscape of osteosarcoma. Nat. Commun. 11, 1008 (2020). Molecular profiling of samples from patients with osteosarcoma characterizes immune subsets, including immune enrichment among older patients. source

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    • cites [43] Lawlor, R. T. et al. Alternative lengthening of telomeres (ALT) influences survival in soft tissue sarcomas: a systematic review with meta-analysis. BMC Cancer 19, 232 (2019). source

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    Premisecitation

    Osteosarcoma cells educate mesenchymal stem cells by secreting TGFβ-containing extracellular vesicles, triggering MSC IL-6 release and activating a STAT3-mediated tumour progression programme that drives formation of metastatic foci in the lung.

    “Osteosarcoma cells educate these MSCs by secreting TGFβ-containing extracellular vesicles 60 , triggering MSC IL-6 release and activating a STAT3-mediated tumour progression programme that drives the formation of metastatic foci within the lung 61 .”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [60] Baglio, S. R. et al. Blocking tumor-educated MSC paracrine activity halts osteosarcoma progression. Clin. Cancer Res. 23, 3721–3733 (2017). source

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    • cites [61] Tu, B., Du, L., Fan, Q. M., Tang, Z. & Tang, T. T. STAT3 activation by IL-6 from mesenchymal stem cells promotes the proliferation and metastasis of osteosarcoma. Cancer Lett. 325, 80–88 (2012). source

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    Premisecitation

    The single most frequently altered gene in osteosarcoma is TP53, which is lost in more than 90% of tumours, with most losses through intron 1 rearrangements or deletions rather than point mutations.

    “The single most frequently altered gene is the tumour suppressor TP53, which is lost in >90% of osteosarcoma tumours, with the majority lost through intron 1 rearrangements or deletions rather than through point mutations 33,36,38 .”
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    • cites [33] Chen, X. et al. Recurrent somatic structural variations contribute to tumorigenesis in pediatric osteosarcoma. Cell Rep. 7, 104–112 (2014). The majority of TP53 loss in osteosarcoma occurs through intron 1 rearrangements or deletions rather than through point mutations. source

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    • cites [36] Wu, C. C. et al. Immuno-genomic landscape of osteosarcoma. Nat. Commun. 11, 1008 (2020). Molecular profiling of samples from patients with osteosarcoma characterizes immune subsets, including immune enrichment among older patients. source

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    • cites [38] Behjati, S. et al. Recurrent mutation of IGF signalling genes and distinct patterns of genomic rearrangement in osteosarcoma. Nat. Commun. 8, 15936 (2017). source

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    Premisecitation

    The dialogue between osteosarcoma cells and their microenvironment is crucial for tumour growth at the bone site and involves direct interactions among mesenchymal, vascular and immune cells, soluble factors such as chemokines and cytokines, and extracellular vesicles.

    “The dialogue between osteosarcoma cells and their microenvironment is crucial for tumour growth at the bone site and is associated with direct interaction among mesenchymal, vascular and immune cells (depending on cell differentiation level) 45 , the interaction of cells with soluble factors such as chemokines and cytokines 46 , and the interaction of cells with extracellular vesicles 47 .”
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    • cites [45] Tellez-Gabriel, M. et al. Analysis of gap junctional intercellular communications using a dielectrophoresis-based microchip. Eur. J. Cell Biol. 96, 110–118 (2017). source

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    • cites [46] Bénédicte Brounais, L.-R. & Frédéric, L. In Bone Cancer 221–239, Ch. 18 (Academic Press, 2022).

      Not checked in the free run.

    • cites [47] Lan, M. et al. Extracellular vesicles-mediated signaling in the osteosarcoma microenvironment: roles and potential therapeutic targets. J. Bone Oncol. 12, 101–104 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The seed and soil phenomenon in osteosarcoma is driven by a microenvironment that modulates osteosarcoma cell behaviour and facilitates proliferation, quiescence, invasion, migration and drug resistance, and contributes to intrinsic heterogeneity.

    “This seed and soil phenomenon is driven by a microenvironment that modulates osteosarcoma cell behaviour and facilitates proliferation, quiescence, invasion, migration, and drug resistance 15,51,52,53 and contributes to their intrinsic heterogeneity 54,55 .”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [15] Brown, H. K., Schiavone, K., Gouin, F., Heymann, M.-F. & Heymann, D. Biology of bone sarcomas and new therapeutic developments. Calcif. Tissue Int. 102, 174–195 (2018). source

      Not checked in the free run.

    • cites [51] Heymann, M.-F., Lézot, F. & Heymann, D. The contribution of immune infiltrates and the local microenvironment in the pathogenesis of osteosarcoma. Cell. Immunol. https://doi.org/10.1016/j.cellimm.2017.10.011 (2017). source

      Not checked in the free run.

    • cites [52] Brown, H. K., Tellez-Gabriel, M. & Heymann, D. Cancer stem cells in osteosarcoma. Cancer Lett. 386, 189–195 (2017). source

      Not checked in the free run.

    • cites [53] Grunewald, T. G. et al. Sarcoma treatment in the era of molecular medicine. EMBO Mol. Med. 12, e11131 (2020). source

      Not checked in the free run.

    • cites [54] Zhou, Y. et al. Single-cell RNA landscape of intratumoral heterogeneity and immunosuppressive microenvironment in advanced osteosarcoma. Nat. Commun. 11, 6322 (2020). source

      Not checked in the free run.

    • cites [55] Guo, J. et al. Single-cell profiling of tumor microenvironment heterogeneity in osteosarcoma identifies a highly invasive subcluster for predicting prognosis. Front. Oncol. 12, 732862 (2022). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Large-scale sequencing has identified only moderate levels of point mutations in osteosarcoma, with few recurrently mutated genes.

    “large-scale sequencing has identified only moderate levels of point mutations with few recurrently mutated genes 33,34,36,38 .”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [33] Chen, X. et al. Recurrent somatic structural variations contribute to tumorigenesis in pediatric osteosarcoma. Cell Rep. 7, 104–112 (2014). The majority of TP53 loss in osteosarcoma occurs through intron 1 rearrangements or deletions rather than through point mutations. source

      Not checked in the free run.

    • cites [34] Perry, J. A. et al. Complementary genomic approaches highlight the PI3K/mTOR pathway as a common vulnerability in osteosarcoma. Proc. Natl Acad. Sci. USA 111, E5564–E5573 (2014). source

      Not checked in the free run.

    • cites [36] Wu, C. C. et al. Immuno-genomic landscape of osteosarcoma. Nat. Commun. 11, 1008 (2020). Molecular profiling of samples from patients with osteosarcoma characterizes immune subsets, including immune enrichment among older patients. source

      Not checked in the free run.

    • cites [38] Behjati, S. et al. Recurrent mutation of IGF signalling genes and distinct patterns of genomic rearrangement in osteosarcoma. Nat. Commun. 8, 15936 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The overall role of osteoclasts in osteosarcoma development remains unclear, as they seem to have a pro-tumorigenic role in early-stage disease but an opposite role in later-stage disease.

    “However, the overall role of osteoclasts in osteosarcoma development remains unclear as they seem to hold a pro-tumorigenic role in early-stage disease 48 but an opposite role in later-stage disease 49 .”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [48] Cackowski, F. C. et al. Osteoclasts are important for bone angiogenesis. Blood 115, 140–149 (2010). source

      Not checked in the free run.

    • cites [49] Endo-Munoz, L., Evdokiou, A. & Saunders, N. A. The role of osteoclasts and tumour-associated macrophages in osteosarcoma metastasis. Biochim. Biophys. Acta 1826, 434–442 (2012).

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The most likely order of events for osteosarcoma evolution is loss of TP53 and RB1 as early events, with TP53 loss likely initiating genomic instability, followed by whole-genome doubling, gain of 8q (CMYC) and loss of 10q (PTEN).

    “The most likely order of events for osteosarcoma evolution is loss of TP53 and RB1 as early events, of which TP53 loss is likely the initiator of genomic instability 39,40,41 followed by whole-genome doubling, gain of 8q (CMYC) and loss of 10q (PTEN) 42 .”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [39] Overholtzer, M. et al. The presence of p53 mutations in human osteosarcomas correlates with high levels of genomic instability. Proc. Natl Acad. Sci. USA 100, 11547–11552 (2003). One of the first studies to show that p53 mutations correlate with high levels of genomic instability in osteosarcomas. source

      Not checked in the free run.

    • cites [40] Eischen, C. M. Genome stability requires p53. Cold Spring Harb. Perspect. Med. 6, a026096 (2016). source

      Not checked in the free run.

    • cites [41] Hanel, W. & Moll, U. M. Links between mutant p53 and genomic instability. J. Cell. Biochem. 113, 433–439 (2012). source

      Not checked in the free run.

    • cites [42] Gerstung, M. et al. The evolutionary history of 2,658 cancers. Nature 578, 122–128 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The cytoskeletal linker ezrin provides a scaffold for PI3K-AKT signalling and facilitates survival through stresses that disseminated tumour cells first encounter within the lung.

    “The cytoskeletal linker ezrin provides a scaffold for PI3K-AKT signalling and facilitates survival through the stresses that disseminated tumour cells first encounter within the lung 72,73,74 .”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [72] Khanna, C. et al. The membrane-cytoskeleton linker ezrin is necessary for osteosarcoma metastasis. Nat. Med. 10, 182–186 (2004). source

      Not checked in the free run.

    • cites [73] Bulut, G. et al. Small molecule inhibitors of ezrin inhibit the invasive phenotype of osteosarcoma cells. Oncogene 31, 269–281 (2012). source

      Not checked in the free run.

    • cites [74] Ren, L. et al. Dysregulation of Ezrin phosphorylation prevents metastasis and alters cellular metabolism in osteosarcoma. Cancer Res. 72, 1001–1012 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mesenchymal stem cells have been implicated in osteosarcoma metastasis and therapeutic resistance.

    “Mesenchymal stem cells (MSCs) have been implicated in osteosarcoma metastasis and therapeutic resistance 57,58,59 .”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [57] Stamatopoulos, A. et al. Mesenchymal stromal cells for bone sarcoma treatment: roadmap to clinical practice. J. Bone Oncol. 16, 100231 (2019). source

      Not checked in the free run.

    • cites [58] Perrot, P. et al. Safety concern between autologous fat graft, mesenchymal stem cell and osteosarcoma recurrence. PLoS ONE 5, e10999 (2010). source

      Not checked in the free run.

    • cites [59] Cortini, M., Avnet, S. & Baldini, N. Mesenchymal stroma: role in osteosarcoma progression. Cancer Lett. 405, 90–99 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Loss of TP53 and RB1 likely occurs early in osteosarcoma transformation, with TP53 inactivation required to propagate abnormal genomes, followed by rapid accumulation of driver lesions such as MYC amplification, PTEN loss and deletion of ATRX.

    “Using these genomic aberrations to infer the evolution of the tumours, loss of TP53 and RB1 likely occurs early in the transformation process (with TP53 inactivation required to propagate abnormal genomes 39,40,41 ), followed by rapid accumulation of driver lesions such as MYC amplification, PTEN loss 42 and deletion of ATRX”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [39] Overholtzer, M. et al. The presence of p53 mutations in human osteosarcomas correlates with high levels of genomic instability. Proc. Natl Acad. Sci. USA 100, 11547–11552 (2003). One of the first studies to show that p53 mutations correlate with high levels of genomic instability in osteosarcomas. source

      Not checked in the free run.

    • cites [40] Eischen, C. M. Genome stability requires p53. Cold Spring Harb. Perspect. Med. 6, a026096 (2016). source

      Not checked in the free run.

    • cites [41] Hanel, W. & Moll, U. M. Links between mutant p53 and genomic instability. J. Cell. Biochem. 113, 433–439 (2012). source

      Not checked in the free run.

    • cites [42] Gerstung, M. et al. The evolutionary history of 2,658 cancers. Nature 578, 122–128 (2020). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Skeletal imaging with PET or technetium bone scans is important to identify covert bony disease.

    “Skeletal imaging with PET or technetium bone scans is important to identify covert bony disease 107 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [107] Meyer, J. S. et al. Imaging guidelines for children with Ewing sarcoma and osteosarcoma: a report from the Children’s Oncology Group Bone Tumor Committee. Pediatr. Blood Cancer 51, 163–170 (2008). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Staging is guided primarily by the MSTS staging system for sarcomas, which defines tumours as low or high grade, confined to an anatomic compartment or violating barriers, and localized or metastatic.

    “Staging is guided primarily by the Musculoskeletal Tumour Society (MSTS) staging system for sarcomas 108 , which defines tumours as being either low or high grade, confined to an anatomic compartment or violating anatomic barriers, and localized or metastatic.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [108] Wolf, R. E. & Enneking, W. F. The staging and surgery of musculoskeletal neoplasms. Orthop. Clin. North. Am. 27, 473–481 (1996). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Response to neoadjuvant chemotherapy, assessed in the definitive resection specimen, has clear prognostic value and has been used to stratify patients into good and poor responders.

    “The response to neoadjuvant chemotherapy, assessed in the definitive resection specimen, has clear prognostic value and has been used in previous clinical trials to stratify patients into good responders and poor responders; however, intensification of treatment did not improve outcomes in the poor responder group 114 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [114] Marina, N. M. et al. Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial. Lancet Oncol. 17, 1396–1408 (2016). An international randomized clinical trial fails to show benefit of addition of I/E to MAP chemotherapy in the primary treatment of osteosarcoma. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Loss of structural integrity due to tumour-related osteolysis puts patients with osteosarcoma at risk for pathological fractures, which occur in about 10% of patients and can complicate initial management.

    “The loss of structural integrity due to tumour-related osteolysis puts patients at risk for pathological fractures, which occur in ~10% of patients and can complicate initial management 102 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [102] Zhou, Y. et al. The effect of pathological fractures on the prognosis of patients with osteosarcoma: a meta-analysis of 14 studies. Oncotarget 8, 73037–73049 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IGF1 receptor amplifications occur in up to 14% of patients with osteosarcoma and seem to drive activation of the PI3K-AKT-mTOR pathway through the MAPK pathway.

    “Indeed, IGF1 receptor amplifications occur in up to 14% of patients with osteosarcoma 38 , which seems to drive activation of the PI3K-AKT-mTOR pathway through the MAPK pathway 98 .”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [38] Behjati, S. et al. Recurrent mutation of IGF signalling genes and distinct patterns of genomic rearrangement in osteosarcoma. Nat. Commun. 8, 15936 (2017). source

      Not checked in the free run.

    • cites [98] Li, Y. S., Liu, Q., He, H. B. & Luo, W. The possible role of insulin-like growth factor-1 in osteosarcoma. Curr. Probl. Cancer 43, 228–235 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Copy number amplifications of potentially targetable genes seemed to predict sensitivity to specific agents, but subsequent work has shown that the picture is much more complicated.

    “Copy number amplifications of potentially targetable genes seemed to predict sensitivity to specific agents 35 ; however, subsequent work has shown that the picture is much more complicated 9 .”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [35] Sayles, L. C. et al. Genome-informed targeted therapy for osteosarcoma. Cancer Discov. 9, 46–63 (2019). A study that defines potentially actionable molecular subtypes of osteosarcoma. source

      Not checked in the free run.

    • cites [9] Gill, J. & Gorlick, R. Advancing therapy for osteosarcoma. Nat. Rev. Clin. Oncol. 18, 609–624 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The promising preclinical successes seen with CDK12 inhibitors and drugs that block protein elongation may not be surprising because osteosarcoma cells depend on massive levels of protein production.

    “The promising preclinical successes seen with CDK12 inhibitors 92 and drugs that block protein elongation 93 may not be surprising as osteosarcoma cells depend on massive levels of protein production.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [92] Bayles, I. et al. Ex vivo screen identifies CDK12 as a metastatic vulnerability in osteosarcoma. J. Clin. Invest. 129, 4377–4392 (2019). source

      Not checked in the free run.

    • cites [93] Chang, L.-S. et al. Targeting protein translation by rocaglamide and didesmethylrocaglamide to treat MPNST and other sarcomas. Mol. Cancer Ther. 19, 731–741 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Patients with osteosarcoma who experience fractures have higher rates of lung metastasis both at presentation and after treatment.

    “Patients experiencing fractures have higher rates of lung metastasis, both at presentation and subsequent to treatment 102 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [102] Zhou, Y. et al. The effect of pathological fractures on the prognosis of patients with osteosarcoma: a meta-analysis of 14 studies. Oncotarget 8, 73037–73049 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Most osteosarcoma patients present with high-grade lesions with bony and soft tissue components, making metastasis presence the primary risk-stratifying feature at diagnosis.

    “Most patients present with high-grade lesions that have both bony and soft tissue components, making the presence or absence of metastasis the primary risk-stratifying feature at diagnosis.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Most osteosarcoma patients present with high-grade lesions that have both bony and soft tissue components.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    Adequate tissue sampling must be ensured for core needle biopsies because osteosarcoma lesions are heterogeneous and diagnostic features vary between samples.

    “For core needle biopsies, adequate sampling of the tissue has to be ensured as osteosarcoma lesions can be quite heterogeneous and diagnostic features (such as malignant osteoid) can vary from sample to sample.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Osteosarcoma lesions are heterogeneous and diagnostic features such as malignant osteoid vary from sample to sample.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The 2008 Children's Oncology Group guidelines, still widely accepted, advocate PET imaging with whole-body CT or MRI, and isotope bone scans if those modalities are unavailable.

    “In 2008, guidelines from the Children's Oncology Group were published 107 , and are still widely accepted, advocating PET imaging with accompanying whole-body CT or whole-body MRI, with isotope bone scans if these modalities are not available.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [107] Meyer, J. S. et al. Imaging guidelines for children with Ewing sarcoma and osteosarcoma: a report from the Children’s Oncology Group Bone Tumor Committee. Pediatr. Blood Cancer 51, 163–170 (2008). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    There has been long-standing interest in immune-based therapies centred on the activity of mifamurtide in osteosarcoma in phase II and a randomized phase III trial conducted by the Children's Oncology Group.

    “There has been a long-standing interest in immune-based therapies centred on the activity of mifamurtide in osteosarcoma in phase II and subsequently on a randomized phase III trial conducted by the Children's Oncology Group 81 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [81] Meyers, P. A. et al. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival — a report from the Children’s Oncology Group. J. Clin. Oncol. 26, 633–638 (2008). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A small number of patients present with localized, lower-grade parosteal and periosteal lesions.

    “A small number of patients present with localized, lower-grade parosteal and periosteal lesions 109,110 .”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [109] Sheth, D. S. et al. Conventional and dedifferentiated parosteal osteosarcoma. Diagnosis, treatment, and outcome. Cancer 78, 2136–2145 (1996). source

      Not checked in the free run.

    • cites [110] Grimer, R. J. et al. Periosteal osteosarcoma — a European review of outcome. Eur. J. Cancer 41, 2806–2811 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Patients with lung metastasis have the worst prognosis, with 3-year survival rates below 30%.

    “Patients who present with lung metastasis have the worst prognosis, with 3-year survival rates of <30% 113 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [113] Aljubran, A. H., Griffin, A., Pintilie, M. & Blackstein, M. Osteosarcoma in adolescents and adults: survival analysis with and without lung metastases. Ann. Oncol. 20, 1136–1141 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The genomic complexity of osteosarcoma might suggest sensitivity to immune modulators such as immune-checkpoint inhibitors, but the overall mutational burden within most osteosarcomas is markedly less than that associated with responses to immune-checkpoint inhibition in other adult tumours.

    “The genomic complexity of osteosarcoma might suggest sensitivity to immune modulators such as immune-checkpoint inhibitors (ICIs) but the overall mutational burden within most osteosarcomas is markedly less than that associated with responses to immune-checkpoint inhibition in other adult tumours 83 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [83] Gröbner, S. N. et al. The landscape of genomic alterations across childhood cancers. Nature 555, 321–327 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Fine-needle aspirates are usually inadequate for definitive osteosarcoma diagnosis because they lack sufficient histological context and make tumour grade assessment difficult.

    “Fine-needle aspirates are usually inadequate for a definitive diagnosis of osteosarcoma due to the lack of sufficient histological context and the resulting difficulty to assess tumour grade, and are therefore not recommended.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Fine-needle aspirates lack sufficient histological context and make tumour grade assessment difficult.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The definition of good and poor responder to chemotherapy varies depending on the study.

    “The definition of good responder and poor responder to chemotherapy varies depending on the study.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [115] Rosen, G., Murphy, M. L., Huvos, A. G., Gutierrez, M. & Marcove, R. C. Chemotherapy, en bloc resection, and prosthetic bone replacement in the treatment of osteogenic sarcoma. Cancer 37, 1–11 (1976). source

      Not checked in the free run.

    • cites [116] Rosen, G. et al. Preoperative chemotherapy for osteogenic sarcoma: selection of postoperative adjuvant chemotherapy based on the response of the primary tumor to preoperative chemotherapy. Cancer 49, 1221–1230 (1982). source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisenone given

    All patients with newly diagnosed osteosarcoma should undergo CT imaging of the chest, which has the highest efficiency in identifying lung nodules.

    “All patients presenting with newly diagnosed disease should undergo CT imaging of the chest, which has the highest efficiency in identifying lung nodules (Fig. 6g).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The workup for presenting symptoms of osteosarcoma usually includes plain-film radiographs, which may reveal large lesions causing destruction of normal trabecular bone with poorly defined margins.

    “The workup for the presenting symptoms usually includes plain-film radiographs, potentially revealing large lesions that are causing destruction of normal trabecular bone with poorly defined margins 103”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [103] Papagelopoulos, P. J. et al. Current concepts in the evaluation and treatment of osteosarcoma. Orthopedics 23, 858–867 (2000). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Local recurrence rates for extremity osteosarcoma are low and generally less than 5%, suggesting that complete resection is achieved in most cases.

    “Local recurrence rates for extremity osteosarcoma are low and generally less than 5%, suggesting that, in most cases, complete resection is achieved.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    Combination chemotherapy and complete surgical resection are essential for cure in both localized and primary metastatic osteosarcoma, provided complete surgical removal of all known metastatic deposits has been achieved.

    “This applies to both patients with localized disease and those with primary metastatic osteosarcoma, provided complete surgical removal of all known metastatic deposits has been achieved.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Combination chemotherapy and complete surgical resection are essential for cure in osteosarcoma.

  • May combine two claims.

    Premisecitation

    Some studies suggested that chondroblastic and telangiectatic histological subtypes have less necrosis, but those differences have not translated into improved survival.

    “Some studies suggested that the histological subtype of osteosarcoma can influence the degree of necrosis, with chondroblastic and telangiectatic subtypes having less necrosis but those differences have not translated into improvement in survival 1,118 .”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] Mirabello, L., Troisi, R. J. & Savage, S. A. Osteosarcoma incidence and survival rates from 1973 to 2004: data from the surveillance, epidemiology, and end results program. Cancer 115, 1531–1543 (2009). source

      Not checked in the free run.

    • cites [118] Bacci, G. et al. Neoadjuvant chemotherapy for high-grade central osteosarcoma of the extremity. Cancer 97, 3068–3075 (2003). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    No specific blood-based biomarkers or routine imaging for screening and early detection of osteosarcoma exist.

    “No specific blood-based biomarkers or routine imaging for screening and early detection of osteosarcoma exist.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    Low-grade osteosarcoma lesions, including low-grade central lesions, are treated by local surgical control only.

    “Low-grade lesions, including low-grade central lesions, are treated by local surgical control only.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Molecular features that identify patients at higher risk include RB1 loss, MYC amplification and VEGFA amplification, among others.

    “Molecular features that identify patients at higher risk include RB1 loss, MYC amplification and VEGFA amplification, among others.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Considerable chemotherapy-related toxic effects were observed in the EURO-B.O.S.S. study, with neutropenia and other haematological adverse effects most frequent.

    “However, considerable chemotherapy-related toxic effects were observed; neutropenia and other haematological adverse effects were most frequent.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [133] Ferrari, S. et al. EURO-B.O.S.S.: a European study on chemotherapy in bone-sarcoma patients aged over 40: Outcome in primary high-grade osteosarcoma. Tumori 104, 30–36 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Identification of individuals at risk enables adherence to clinical practice guidelines and early identification and risk reduction for osteosarcoma and other cancers.

    “Identification of individuals at risk enables adherence to clinical practice guidelines and early identification and risk reduction for osteosarcoma as well as other cancers 120 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [120] Villani, A. et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study. Lancet Oncol. 17, 1295–1305 (2016). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Limb salvage is feasible for most patients with extremity tumours via reconstruction using an endoprosthetic implant, or allogeneic or autologous bone graft.

    “Limb salvage is feasible for most patients with extremity tumours via reconstruction using an endoprosthetic implant, or allogeneic or autologous bone graft.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The most efficacious regimens employ at least three of these drugs, yet adding a fourth agent may not lead to further benefits.

    “The most efficacious regimens employ at least three of these drugs, yet adding a fourth agent may not lead to further benefits 128 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [128] Anninga, J. K. et al. Chemotherapeutic adjuvant treatment for osteosarcoma: where do we stand? Eur. J. Cancer 47, 2431–2445 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Because therapy changes based on necrosis grading have not been shown to modify survival outcomes, the use of necrosis grading has declined.

    “Given that therapy changes based on necrosis grading have not been shown to modify survival outcomes, the use of necrosis grading has declined.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Patients with unresectable primary or metastatic disease at diagnosis and those with disease relapse have extremely poor outcomes.

    “In addition, patients with unresectable primary or metastatic disease at diagnosis and those with disease relapse have extremely poor outcomes 2,126 .”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [2] Bielack, S. S. et al. Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J. Clin. Oncol. 20, 776–790 (2002). A study that affirms tumour site and size, primary metastases, response to chemotherapy, and surgical remission as independent prognostic factors in patients with osteosarcoma. source

      Not checked in the free run.

    • cites [126] Kempf-Bielack, B. et al. Osteosarcoma relapse after combined modality therapy: an analysis of unselected patients in the Cooperative Osteosarcoma Study Group (COSS). J. Clin. Oncol. 23, 559–568 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Prognosis improvement seems linear with increasing necrosis, with some studies setting the good/poor cut-off between grades 2 and 3 and others between grades 3 and 4.

    “The improvement in prognosis seems linear with increasing necrosis, with some studies setting the cut-off point between good and poor between grades 2 and 3, whereas others have set it between grades 3 and 4.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [117] Bishop, M. W. et al. Assessing the prognostic significance of histologic response in osteosarcoma: a comparison of outcomes on CCG-782 and INT0133 — a report from the Children’s Oncology Group Bone Tumor Committee. Pediatr. Blood Cancer 63, 1737–1743 (2016). This study validates the prognostic significance of pathological treatment response in osteosarcoma following neoadjuvant chemotherapy. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    Intermediate-grade osteosarcoma lesions, including periosteal lesions and most osteosarcomas affecting the jaw, need local control, typically surgery.

    “Intermediate-grade lesions, including periosteal lesions and most osteosarcomas that affect the jaw, similarly need local control, which is also typically surgery.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Minimally invasive and non-invasive growing implants enable limb-salvage reconstruction and future limb-length equality for patients with skeletal immaturity.

    “Minimally invasive and non-invasive growing implants enable limb-salvage reconstruction as well as future limb-length equality for patients with skeletal immaturity 135 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [135] Ruggieri, P. et al. Outcome of expandable prostheses in children. J. Pediatr. Orthop. 33, 244–253 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Intralesional or marginal resections increase local recurrence rate, which is associated with reduced overall survival.

    “Otherwise, intralesional or marginal resections increase local recurrence rate, which is associated with reduced overall survival 2,134 .”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [2] Bielack, S. S. et al. Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J. Clin. Oncol. 20, 776–790 (2002). A study that affirms tumour site and size, primary metastases, response to chemotherapy, and surgical remission as independent prognostic factors in patients with osteosarcoma. source

      Not checked in the free run.

    • cites [134] Picci, P. et al. Relationship of chemotherapy-induced necrosis and surgical margins to local recurrence in osteosarcoma. J. Clin. Oncol. 12, 2699–2705 (1994). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Guidelines for patients and families with Li-Fraumeni syndrome include annual whole-body MRI to screen for multiple possible malignancies, including sarcomas, and maintaining a high index of suspicion for rare cancers.

    “Guidelines for patients and families with Li-Fraumeni syndrome include annual whole-body MRI to screen for multiple possible malignancies, including sarcomas, and maintaining a high index of suspicion for rare cancers 122 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [122] Kratz, C. P. et al. Cancer screening recommendations for individuals with Li-Fraumeni syndrome. Clin. Cancer Res. 23, e38–e45 (2017). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisereasoning

    Osteosarcomas in other craniofacial locations can be high grade and are treated with chemotherapy and local control.

    “Osteosarcomas in other craniofacial locations can be high grade, and are treated with chemotherapy and local control in such case.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Intensive blood and imaging-based surveillance in patients with pathogenic germline TP53 variants has been shown to be feasible, detects solid tumours at an earlier stage, and is associated with improved long-term survival, although these findings were not specific to osteosarcoma.

    “Intensive blood and imaging-based surveillance in patients with pathogenic germline TP53 variants has been shown to be feasible, resulting in the detection of solid tumours at an earlier stage and associated with improved long-term survival, although these findings were not specific to osteosarcoma 120 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [120] Villani, A. et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study. Lancet Oncol. 17, 1295–1305 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    There is no standard-of-care systemic therapy for patients >40 years of age with osteosarcoma, and few clinical trials inform practice.

    “There is no standard-of-care systemic therapy for patients >40 years of age with a poor outcome and few clinical trials to inform practice 132 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [132] Grimer, R. J. et al. Osteosarcoma over the age of forty. Eur. J. Cancer 39, 157–163 (2003). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The number of metastases and completeness of excision seem to affect outcomes.

    “Here, the number of metastases and completeness of excision seem to affect outcomes 6 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Kager, L. et al. Primary metastatic osteosarcoma: presentation and outcome of patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols. J. Clin. Oncol. 21, 2011–2018 (2003). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Progress in osteosarcoma was made with the introduction of systemic chemotherapy, which was soon administered neoadjuvantly.

    “Progress was only made with the introduction of systemic chemotherapy, which was soon administered neoadjuvantly 127 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [127] Jaffe, N., Puri, A. & Gelderblom, H. Osteosarcoma: evolution of treatment paradigms. Sarcoma 2013, 203531 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Surgery is an important local control modality for metastatic sites, with long-term survival improving with resection of lung metastases.

    “Surgery is also an important local control modality for metastatic sites, with long-term survival improving with the resection of lung metastases.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Retrospective analysis of the European Musculoskeletal Oncology Society of patients over 40 years demonstrated that adult patients may benefit from aggressive treatment with surgery and chemotherapy, with outcomes possibly related to decreased chemotherapy administered to some elderly patients.

    “Retrospective analysis of the European Musculoskeletal Oncology Society of patients over 40 years did demonstrate that adult patients may benefit from aggressive treatment with surgery and chemotherapy, with outcomes possibly being related to decreased chemotherapy administered to some of the elderly patients 132 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [132] Grimer, R. J. et al. Osteosarcoma over the age of forty. Eur. J. Cancer 39, 157–163 (2003). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The dosage of chemotherapy given before surgery shifts the degree of necrosis but does not change the prognostic value of necrosis grading or influence survival.

    “The dosage of chemotherapy given before surgery shifts the degree of necrosis but it does not change the prognostic value of necrosis grading nor influence survival 119 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [119] Meyers, P. A. et al. Intensification of preoperative chemotherapy for osteogenic sarcoma: results of the Memorial Sloan-Kettering (T12) protocol. J. Clin. Oncol. 16, 2452–2458 (1998). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    For intermediate-grade osteosarcomas, the role of chemotherapy is controversial and not associated with the same risk-to-benefit relationship as high-grade osteosarcomas.

    “For intermediate-grade osteosarcomas, the role of chemotherapy is controversial and certainly not associated with the same risk-to-benefit relationship as high-grade osteosarcomas.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Necrosis grading had four levels, each defined descriptively, and percentages were added later to facilitate comparison.

    “For example, necrosis grading had four levels but each level was only defined descriptively 115,116 and percentages were added later to facilitate comparison 116 .”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [115] Rosen, G., Murphy, M. L., Huvos, A. G., Gutierrez, M. & Marcove, R. C. Chemotherapy, en bloc resection, and prosthetic bone replacement in the treatment of osteogenic sarcoma. Cancer 37, 1–11 (1976). source

      Not checked in the free run.

    • cites [116] Rosen, G. et al. Preoperative chemotherapy for osteogenic sarcoma: selection of postoperative adjuvant chemotherapy based on the response of the primary tumor to preoperative chemotherapy. Cancer 49, 1221–1230 (1982). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Treatment for anthracycline-induced heart failure is similar to that of heart failure from any cause.

    “Treatment for anthracycline-induced heart failure is similar to that of heart failure from any cause 164 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [164] Armenian, S. H. et al. Recommendations for cardiomyopathy surveillance for survivors of childhood cancer: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group. Lancet Oncol. 16, e123–e136 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Ablative surgery may be associated with poor joint function but usually involves fewer episodes of revision surgery than limb salvage.

    “Ablative surgery (amputation) may be associated with poor joint function but usually involves fewer episodes of revision surgery than limb salvage.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Osteosarcoma recurs most often in the lung, followed by bone at a site distant to the primary tumour.

    “Osteosarcoma recurs most often in the lung followed by bone at a site distant to the primary tumour.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The cumulative anthracycline dose is a major risk factor for severe cardiomyopathy development, but young age at treatment, female sex, peak drug exposure and additional stress to the heart have also been implicated.

    “The cumulative anthracycline dose is a major risk factor for severe cardiomyopathy development but young age at treatment, female sex, peak drug exposure and additional stress to the heart have also been implicated 161,162,163 .”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [161] Mancilla, T. R., Iskra, B. & Aune, G. J. Doxorubicin-induced cardiomyopathy in children. Compr. Physiol. 9, 905–931 (2019). source

      Not checked in the free run.

    • cites [162] Bhagat, A. & Kleinerman, E. S. Anthracycline-induced cardiotoxicity: causes, mechanisms, and prevention. Adv. Exp. Med. Biol. 1257, 181–192 (2020). source

      Not checked in the free run.

    • cites [163] Rawat, P. S., Jaiswal, A., Khurana, A., Bhatti, J. S. & Navik, U. Doxorubicin-induced cardiotoxicity: an update on the molecular mechanism and novel therapeutic strategies for effective management. Biomed. Pharmacother. 139, 111708 (2021). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The recommended recurrence regimens include high-dose ifosfamide with or without etoposide and gemcitabine and docetaxel.

    “The regimens include high-dose ifosfamide with or without etoposide and gemcitabine and docetaxel.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [104] Strauss, S. J. et al. Bone sarcomas: ESMO-EURACAN-GENTURIS-ERN PaedCan Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann. Oncol. 32, 1520–1536 (2021). source

      Not checked in the free run.

    • cites [141] NCCN. Treatment by cancer type. NCCN https://www.nccn.org/guidelines/category_1 (2022).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Li-Fraumeni syndrome is the most prominent genetic predisposition syndrome in osteosarcoma, but hereditary retinoblastoma, helicase-associated cancers and others also contribute.

    “Among all paediatric patients with cancer, those with osteosarcoma carry one of the highest rates of genetic cancer predisposition (10-20%) 12 ; Li-Fraumeni syndrome is the most prominent but hereditary retinoblastoma, helicase-associated cancers and others also contribute 157 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [157] Kratz, C. P. et al. Predisposition to cancer in children and adolescents. Lancet Child Adolesc. Health 5, 142–154 (2021). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Anthracycline-induced severe cardiomyopathy is a common, potentially fatal late effect of chemotherapy, with ~2% of non-relapse-related deaths among childhood cancer survivors attributed to cardiomyopathy or heart failure.

    “Anthracycline-induced, severe cardiomyopathy is another common, potentially fatal late effect of chemotherapy, with ~2% of non-relapse-related deaths among childhood cancer survivors attributed to cardiomyopathy or heart failure 160 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [160] Armstrong, G. T. et al. Late mortality among 5-year survivors of childhood cancer: a summary from the childhood cancer survivor study. J. Clin. Oncol. 27, 2328–2338 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Trials combining immune checkpoint inhibitors with other anticancer therapies, such as MTKIs, and trials of other immune activation approaches, such as antibody combinations and cellular therapy, in individuals with osteosarcoma are in early stages.

    “Trials combining ICIs with other anticancer therapies, such as MTKIs, and trials of other immune activation approaches, such as antibody combinations and cellular therapy, in individuals with osteosarcoma are in early stages 9 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Gill, J. & Gorlick, R. Advancing therapy for osteosarcoma. Nat. Rev. Clin. Oncol. 18, 609–624 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Local recurrence is rare; it accounted for only 7% of all events in almost 1,000 patients who had an event in EURAMOS-1.

    “Local recurrence is rare; for example, it accounted for only 7% of all events in almost 1,000 patients who had an event in EURAMOS-1 (ref.125 ).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [125] Smeland, S. et al. Survival and prognosis with osteosarcoma: outcomes in more than 2000 patients in the EURAMOS-1 (European and American Osteosarcoma Study) cohort. Eur. J. Cancer 109, 36–50 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The phase I trial of ifosfamide and etoposide plus lenvatinib demonstrated tolerability and a 4-month PFS of 51%.

    “The phase I trial of this combination demonstrated tolerability and a 4-month PFS of 51% 150 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [150] Gaspar, N. et al. Lenvatinib with etoposide plus ifosfamide in patients with refractory or relapsed osteosarcoma (ITCC-050): a multicentre, open-label, multicohort, phase 1/2 study. Lancet Oncol. 22, 1312–1321 (2021). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    The mechanism of action of MTKIs in osteosarcoma is still not well understood and correlative translational studies have yet to identify predictive biomarkers of response to MTKIs.

    “The mechanism of action of MTKIs in osteosarcoma is still not well understood and correlative translational studies have yet to identify predictive biomarkers of response to MTKIs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    These genomic features include the presence of COSMIC mutational signature 3, possibly representing defective DNA damage response in osteosarcoma, in ~30% of cases, and frequent genomic events that lead to replication stress such as MYC amplification and CCNE1 amplification.

    “These features include the presence of COSMIC mutational signature 3 (ref. 154 ), possibly representing defective DNA damage response in osteosarcoma, in ~30% of cases, and the frequent presence of genomic events that lead to replication stress such as MYC amplification and CCNE1 amplification.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [154] Alexandrov, L. B. et al. The repertoire of mutational signatures in human cancer. Nature 578, 94–101 (2020). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Even the most modern endoprostheses have a limited lifespan as mechanical wear or infections require repeated operations in most patients who undergo limb salvage.

    “Even the most modern endoprostheses have a limited lifespan as mechanical wear or infections require repeated operations in most patients who undergo limb salvage.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Secondary cancers are frequently acute myeloid leukaemias, which may be caused by previous exposure to DNA-damaging alkylators, often arising after a median of around 7 years after initial treatment.

    “Secondary cancers are frequently acute myeloid leukaemias 155 , which may be caused by previous exposure to DNA-damaging alkylators, often arising after a median of around 7 years after initial treatment 158 .”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [155] Hecker-Nolting, S., Langer, T., Blattmann, C., Kager, L. & Bielack, S. S. Current insights into the management of late chemotherapy toxicities in pediatric osteosarcoma patients. Cancer Manag. Res. 13, 8989–8998 (2021). source

      Not checked in the free run.

    • cites [158] Leone, G., Pagano, L., Ben-Yehuda, D. & Voso, M. T. Therapy-related leukemia and myelodysplasia: susceptibility and incidence. Haematologica 92, 1389–1398 (2007). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Osteosarcoma surgery is usually associated with loss of a major joint, most often the knee.

    “Osteosarcoma surgery is usually associated with loss of a major joint, most often the knee.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    As a class, multi-target tyrosine kinase inhibitors demonstrate activity in recurrent osteosarcoma and are most often utilized in patients with advanced unresectable disease.

    “As a class, multi-target tyrosine kinase inhibitors (MTKIs) demonstrate activity in recurrent osteosarcoma and are most often utilized in patients with advanced unresectable disease.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    One of the life-threatening late effects of chemotherapy is the development of secondary malignancies, such as therapy-related acute myelogenous leukaemia/myelodysplastic syndrome, central nervous system tumours or secondary solid tumours, which occur in ~3% of patients.

    “One of the life-threatening late effects of chemotherapy is the development of secondary malignancies, such as therapy-related acute myelogenous leukaemia/myelodysplastic syndrome, central nervous system tumours or secondary solid tumours, which occur in ~3% of patients 125 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [125] Smeland, S. et al. Survival and prognosis with osteosarcoma: outcomes in more than 2000 patients in the EURAMOS-1 (European and American Osteosarcoma Study) cohort. Eur. J. Cancer 109, 36–50 (2019). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Allogeneic heart transplants may be indicated for severe cases of anthracycline-induced heart failure.

    “Allogeneic heart transplants may be indicated for severe cases 165,166 .”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [165] Bock, M. J. et al. Cancer recurrence and mortality after pediatric heart transplantation for anthracycline cardiomyopathy: a report from the Pediatric Heart Transplant Study (PHTS) group. Pediatr. Transpl. https://doi.org/10.1111/petr.12923 (2017). source

      Not checked in the free run.

    • cites [166] Shugh, S. B. & Ryan, T. D. Heart transplantation in survivors of childhood cancer. Transl Pediatr. 8, 314–321 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A 4-month PFS of 0% was observed in the control arm of phase II regorafenib trials, and 15% for a historical benchmark from a pooled analysis of 96 patients with osteosarcoma and measurable disease enrolled on seven Children's Oncology Group phase II trials.

    “For comparison, a 4-month PFS of 0% in the control arm of the phase II trials of regorafenib and of 15% for a historical benchmark established by a pooled analysis of 96 patients with osteosarcoma and measurable disease enrolled on seven Children's Oncology Group phase II trials were observed 152 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [152] Lagmay, J. P. et al. Outcome of patients with recurrent osteosarcoma enrolled in seven phase II trials through Children’s Cancer Group, Pediatric Oncology Group, and Children’s Oncology Group: learning from the past to move forward. J. Clin. Oncol. 34, 3031–3038 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Prospective clinical trials evaluated sorafenib, regorafenib, cabozantinib, lenvatinib and apatinib as single agents in patients with relapsed or refractory osteosarcoma, with most enrolled patients in the adult age range.

    “Prospective clinical trials evaluated the MTKIs sorafenib, regorafenib, cabozantinib, lenvatinib and apatinib as single agents in patients with relapsed or refractory osteosarcoma, with most enrolled patients falling in the adult age range 146,147,148,149,150,151 (Table 2).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [146] Davis, L. E. et al. Randomized double-blind phase II study of regorafenib in patients with metastatic osteosarcoma. J. Clin. Oncol. 37, 1424–1431 (2019). source

      Not checked in the free run.

    • cites [147] Grignani, G. et al. A phase II trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of standard multimodal therapy: an Italian Sarcoma Group study. Ann. Oncol. 23, 508–516 (2012). source

      Not checked in the free run.

    • cites [148] Italiano, A. et al. Cabozantinib in patients with advanced Ewing sarcoma or osteosarcoma (CABONE): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 21, 446–455 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Other secondary leukaemias are often myelomonoblastic and have a shorter lag-time; these develop after exposure to topoisomerase II inhibitors, including anthracyclines such as doxorubicin.

    “Other secondary leukaemias are often myelomonoblastic and their lag-time is shorter; these develop after exposure to topoisomerase II inhibitors, including anthracyclines such as doxorubicin.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Curative osteosarcoma treatment, including anthracyclines, alkylating agents and/or topoisomerase II inhibitors, is known to cause secondary malignancies, and the risk is likely increased by individual cancer predisposition and other as yet unidentified factors.

    “Curative osteosarcoma treatment, including anthracyclines, alkylating agents and/or topoisomerase II inhibitors, is known to cause secondary malignancies and the risk is likely increased by individual cancer predisposition and other as yet unidentified factors 155,157 .”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [155] Hecker-Nolting, S., Langer, T., Blattmann, C., Kager, L. & Bielack, S. S. Current insights into the management of late chemotherapy toxicities in pediatric osteosarcoma patients. Cancer Manag. Res. 13, 8989–8998 (2021). source

      Not checked in the free run.

    • cites [157] Kratz, C. P. et al. Predisposition to cancer in children and adolescents. Lancet Child Adolesc. Health 5, 142–154 (2021). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Several chemotherapy regimens are recommended by NCCN and ESMO guidelines at the time of osteosarcoma recurrence.

    “Several chemotherapy regimens are recommended by the National Cancer Care Network (NCCN) and European Society of Medical Oncology (ESMO) guidelines at the time of osteosarcoma recurrence 104,141 .”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [104] Strauss, S. J. et al. Bone sarcomas: ESMO-EURACAN-GENTURIS-ERN PaedCan Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann. Oncol. 32, 1520–1536 (2021). source

      Not checked in the free run.

    • cites [141] NCCN. Treatment by cancer type. NCCN https://www.nccn.org/guidelines/category_1 (2022).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The renal glomerulus might be affected by cisplatin treatment in 60-80% of children and adolescents, and renal tubular function is affected by ifosfamide treatment in 20-25%.

    “The renal glomerulus might be affected by cisplatin treatment in 60-80% of children and adolescents and renal tubular function is affected by ifosfamide treatment in 20-25% 171 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [171] Skinner, R. Late renal toxicity of treatment for childhood malignancy: risk factors, long-term outcomes, and surveillance. Pediatr. Nephrol. 33, 215–225 (2018). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    An increased risk of herpes zoster infection has been found in these individuals and administration of prophylaxis is recommended for patients at risk.

    “An increased risk of herpes zoster infection has been found in those individuals and administration of prophylaxis is recommended for patients at risk 174 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [174] Bader, M. S. Herpes zoster: diagnostic, therapeutic, and preventive approaches. Postgrad. Med. 125, 78–91 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    MTKIs have demonstrated activity in phase II clinical trials and may offer benefit for unresectable or systemic relapse.

    “Multi-target tyrosine kinase inhibitors (TKIs) have demonstrated activity in phase II clinical trials and may offer benefit in this setting.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In this group of osteosarcoma survivors, the burden of physical health conditions was high, with 32% self-reporting impaired physical functioning and 16% reporting impaired general health, considerably worse than matched controls.

    “In this group of patients, the burden of physical health conditions was high, with 32% of osteosarcoma survivors self-reporting impaired physical functioning and 16% reporting impaired general health, which is considerably worse than in matched controls.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [178] Edelmann, M. N. et al. Neurocognitive and patient-reported outcomes in adult survivors of childhood osteosarcoma. JAMA Oncol. 2, 201–208 (2016). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Inner ear damage and permanent hearing loss is a possible incapacitating late chemotherapy effect of cisplatin use, with moderate to severe hearing loss occurring in <30% of patients with osteosarcoma.

    “Inner ear damage and permanent hearing loss is a possible incapacitating late chemotherapy effect of cisplatin use, with moderate to severe hearing loss occurring in <30% of patients with osteosarcoma 168 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [168] Moke, D. J. et al. Prevalence and risk factors for cisplatin-induced hearing loss in children, adolescents, and young adults: a multi-institutional North American cohort study. Lancet Child Adolesc. Health 5, 274–283 (2021). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Well-established cell lines have facilitated investigation into mechanisms of malignancy and high-throughput screens to identify osteosarcoma vulnerabilities.

    “Well-established cell lines, such as SaOS, MG63, KHOS, MNNG-HOS, U2OS and OS-17, have facilitated investigation into mechanisms of malignancy 206,207 and high-throughput screens to identify osteosarcoma vulnerabilities 92,208 .”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [206] Ségaliny, A. I. et al. Interleukin-34 promotes tumor progression and metastatic process in osteosarcoma through induction of angiogenesis and macrophage recruitment. Int. J. Cancer 137, 73–85 (2015). source

      Not checked in the free run.

    • cites [207] Ory, B. et al. Zoledronic acid suppresses lung metastases and prolongs overall survival of osteosarcoma‐bearing mice. Cancer 104, 2522–2529 (2005). source

      Not checked in the free run.

    • cites [92] Bayles, I. et al. Ex vivo screen identifies CDK12 as a metastatic vulnerability in osteosarcoma. J. Clin. Invest. 129, 4377–4392 (2019). source

      Not checked in the free run.

    • cites [208] Dharia, N. V. et al. A first-generation pediatric cancer dependency map. Nat. Genet. 53, 529–538 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Patients who have received intensive, multidrug chemotherapy against osteosarcoma may have reduced antibody titres against vaccine-preventable infections for some months after chemotherapy, and some guidelines suggest measuring vaccine-induced antibody titres and repeating vaccinations.

    “Patients who have received intensive, multidrug chemotherapy against osteosarcoma may have reduced antibody titres against vaccine-preventable infections for some months after chemotherapy, and some guidelines suggest measuring vaccine-induced antibody titres and repeating vaccinations 172,173 .”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [172] Laws, H. J. et al. Impfen bei Immundefizienz : Anwendungshinweise zu den von der Ständigen Impfkommission empfohlenen Impfungen. (III) Impfen bei hämatologischen und onkologischen Erkrankungen (antineoplastische Therapie, Stammzelltransplantation), Organtransplantation und Asplenie [German]. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 63, 588–644 (2020). source

      Not checked in the free run.

    • cites [173] Pittet, L. F. & Posfay-Barbe, K. M. Vaccination of immune compromised children-an overview for physicians. Eur. J. Pediatr. 180, 2035–2047 (2021). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Inhibitors of DNA damage repair include WEE1, PARP, and ATR inhibitors.

    “Inhibitors of DNA damage repair include inhibitors of WEE1, PARP and ATR.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Cisplatin-induced glomerular effects are rarely severe enough to require treatment, but ifosfamide-induced renal tubular effects can lead to clinically relevant electrolyte wasting in the form of Fanconi syndrome.

    “Cisplatin-induced glomerular effects are rarely severe enough to require treatment but ifosfamide-induced renal tubular effects can lead to clinically relevant electrolyte wasting in the form of Fanconi syndrome 171 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [171] Skinner, R. Late renal toxicity of treatment for childhood malignancy: risk factors, long-term outcomes, and surveillance. Pediatr. Nephrol. 33, 215–225 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FDA restrictions were relaxed, so many trials now accept patients aged 12 years and above; most osteosarcoma patients fall into this age range.

    “Due to the loosening of FDA restrictions, many of these trials are now also available for patients aged ≥12 years, which includes most patients with osteosarcoma 192 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [192] FDA. Considerations for the inclusion of adolescent patients in adult oncology clinical trials: guidance for industry. FDA https://bit.ly/2IMiAdT (2019).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A single institution study evaluating HRQoL in 80 survivors at least 10 years after initial diagnosis of osteosarcoma revealed neurocognitive impairment, with significantly lower mean scores in reading skills (P = 0.01), sustained attention (P = 0.002), short-term memory (P = 0.01) and physical processing speed (P < 0.001) compared with matched controls.

    “A single institution study evaluating HRQoL in 80 survivors at least 10 years after the initial diagnosis of osteosarcoma revealed that individuals had neurocognitive impairment, with significantly lower mean scores in reading skills (P = 0.01), sustained attention (P = 0.002), short-term memory (P = 0.01) and physical processing speed (P < 0.001) compared with matched controls 178 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [178] Edelmann, M. N. et al. Neurocognitive and patient-reported outcomes in adult survivors of childhood osteosarcoma. JAMA Oncol. 2, 201–208 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A high proportion of osteosarcoma samples have an increased number of tumour-infiltrating lymphocytes, suggesting immune system activation in many patients with osteosarcoma.

    “A high proportion of osteosarcoma samples have an increased number of tumour-infiltrating lymphocytes, suggesting immune system activation in many patients with osteosarcoma 180 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [180] Koirala, P. et al. Immune infiltration and PD-L1 expression in the tumor microenvironment are prognostic in osteosarcoma. Sci. Rep. 6, 30093 (2016). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Adjuvant chemotherapy's value in unresectable or systemic relapse remains unclear, though it might provide palliative benefit.

    “setting is not well defined but may offer palliative benefit for those with unresectable or systemic relapse.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Fertility is most impaired by alkylators and more so in males than in females.

    “Generally, fertility is most impaired by alkylators and more so in males than in females 175 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [175] van Santen, H. M. et al. Reproductive complications in childhood cancer survivors. Pediatr. Clin. North Am. 67, 1187–1202 (2020). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Surface targets for proteins include HER2 (antibody, ADC, CAR T), GD2 (antibody, CAR T), B7H3 (CAR T), and EGFR (CAR T).

    “Surface targets for the following proteins include HER2: Antibody, ADC, CAR T; GD2: Antibody, CAR T; B7H3: CAR T; EGFR: CAR T.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Palliative chemotherapy, radiotherapy, or both may be offered to patients whose disease is unresectable or widely metastatic.

    “Patients with unresectable and/or widely metastatic disease may receive palliative chemotherapy and/or radiotherapy.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Osteosarcoma can occur in any bone, but the knee area and proximal humerus are the most frequent locations.

    “Osteosarcoma can present in any bone in the body but the most common sites are around the knee and the proximal humerus 201 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [201] Meyers, P. A. & Gorlick, R. Osteosarcoma. Pediatr. Clin. North. Am. 44, 973–989 (1997). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Canine osteosarcoma is very similar to the human disease in its histology, genetics, and clinical course, but it is much more common, with roughly 25,000 new cases annually.

    “Canine osteosarcoma has histological, genetic and clinical features nearly identical to the human disease 232 but has a much higher incidence, with an estimated 25,000 new cases of canine disease occurring each year 232 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [232] Gardner, H. L. et al. Canine osteosarcoma genome sequencing identifies recurrent mutations in DMD and the histone methyltransferase gene SETD2. Commun. Biol. 2, 266 (2019). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Osteosarcoma cells become progressively oligoclonal or polyclonal and form a highly heterogeneous tumour mass.

    “Osteosarcoma (OS) cells become progressively oligoclonal or polyclonal and form a highly heterogeneous tumour mass.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Long-term passage of PDXs in mice can alter tumour behaviour, but strategic use of low-passage lines curbs this mouse-specific drift and remains useful for osteosarcoma biology, precision medicine, and preclinical testing.

    “Although prolonged passage in mice can alter the behaviour of tumours maintained as PDXs 227 , strategic use of low-passage PDX lines limits this mouse-specific evolution and is a useful tool in the study of osteosarcoma biology 228 , precision medicine approaches and preclinical validation of therapeutic candidates.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [227] Ben-David, U. et al. Patient-derived xenografts undergo mouse-specific tumor evolution. Nat. Genet. 49, 1567–1575 (2017). source

      Not checked in the free run.

    • cites [228] Woo, X. Y. et al. Conservation of copy number profiles during engraftment and passaging of patient-derived cancer xenografts. Nat. Genet. 53, 86–99 (2021). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Interaction between cancer and bone cells leads to increased OS cell proliferation and altered bone remodelling.

    “Interaction between cancer and bone cells leads to an increase in OS cell proliferation and altered bone remodelling.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    For resectable high-grade osteosarcoma, treatment requires chemotherapy plus removal of every disease site.

    “Patients with resectable high-grade osteosarcoma require chemotherapy and resection of all sites of disease.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Ex vivo techniques have been adapted to study tumour-host interactions, screen for metastasis-related vulnerabilities, and validate hits from other screens.

    “These techniques have been adapted to study tumour-host interactions, to screen for metastasis-related vulnerabilities and to validate hits identified in other screens 74,75,92,216,217,218,219 .”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [74] Ren, L. et al. Dysregulation of Ezrin phosphorylation prevents metastasis and alters cellular metabolism in osteosarcoma. Cancer Res. 72, 1001–1012 (2012). source

      Not checked in the free run.

    • cites [75] Morrow, J. J. et al. Positively selected enhancer elements endow osteosarcoma cells with metastatic competence. Nat. Med. 24, 176–185 (2018). source

      Not checked in the free run.

    • cites [92] Bayles, I. et al. Ex vivo screen identifies CDK12 as a metastatic vulnerability in osteosarcoma. J. Clin. Invest. 129, 4377–4392 (2019). source

      Not checked in the free run.

    • cites [216] Tsai, Y. C. et al. The ubiquitin ligase gp78 promotes sarcoma metastasis by targeting KAI1 for degradation. Nat. Med. 13, 1504–1509 (2007). source

      Not checked in the free run.

    • cites [217] Lizardo, M. M. et al. Upregulation of glucose-regulated protein 78 in metastatic cancer cells is necessary for lung metastasis progression. Neoplasia 18, 699–710 (2016). source

      Not checked in the free run.

    • cites [218] Morrow, J. J. et al. mTOR inhibition mitigates enhanced mRNA translation associated with the metastatic phenotype of osteosarcoma cells in vivo. Clin. Cancer Res. 22, 6129–6141 (2016). source

      Not checked in the free run.

    • cites [219] Yu, P. Y. et al. Target specificity, in vivo pharmacokinetics, and efficacy of the putative STAT3 inhibitor LY5 in osteosarcoma, Ewing’s sarcoma, and rhabdomyosarcoma. PLoS ONE 12, e0181885 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Osteosarcoma cells release TGFβ-containing extracellular vesicles that activate local mesenchymal stem cells; these then release IL-6-containing vesicles that promote tumour progression.

    “In addition, OS cells activate local mesenchymal stem cells (MSCs) by producing extracellular vesicles (EVs) containing TGFβ, which in turn release EVs containing IL-6, facilitating tumour progression.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Cytokine-containing EVs prepare the lung metastatic niche to receive OS circulating tumour cells.

    “Similarly, cytokine-containing EVs prepare the lung metastatic niche to receive OS circulating tumour cells.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Dogs that develop sporadic osteosarcoma offer a distinctive model for studying tumour biology and treatment, potentially speeding discovery and helping both dogs and humans.

    “Canine companion animals that develop sporadic osteosarcoma present a unique opportunity to study tumour biology and therapy in ways that can accelerate discovery and benefit both species 231 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [231] Fenger, J. M., London, C. A. & Kisseberth, W. C. Canine osteosarcoma: a naturally occurring disease to inform pediatric oncology. ILAR J. 55, 69–85 (2014). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Chemotherapy is usually administered both before and after surgery, but in selected cases surgery can come first, with adjuvant chemotherapy afterward.

    “Both neoadjuvant and adjuvant chemotherapy is usually given but surgery may be considered upfront followed by adjuvant chemotherapy in selected cases.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    For low-grade and intermediate-grade osteosarcoma, treatment consists of surgery only.

    “Low-grade and intermediate-grade osteosarcomas are managed with surgery alone.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    At metastatic sites, cytokines and growth factors aid local tumour growth, and extracellular vesicles seem to be the main way osteosarcoma cells communicate with lung tissue.

    “In the metastatic foci, cytokines and growth factors contribute to the local tumour development and EVs seem to be the main messenger between OS cells and the pulmonary parenchyma.”
    Quote in the paperNot a substantial claim
138 of 138

  • The authors state this as an assumption.

    Osteosarcoma arises from a multipotent mesenchymal precursor.

    “This microscopic phenotype has long fuelled the assumption that osteosarcoma arises from a multipotent mesenchymal precursor.”

  • The paper relies on this without support.

    Population-based screening and surveillance strategies for osteosarcoma have not been implemented because the disease is rare and reliable markers are lacking.

    “So far, population-based screening and surveillance strategies have not been implemented due to the rarity of osteosarcoma and the lack of reliable markers.”

  • The paper relies on this without support.

    Osteosarcoma lesions are heterogeneous and diagnostic features such as malignant osteoid vary from sample to sample.

    “For core needle biopsies, adequate sampling of the tissue has to be ensured as osteosarcoma lesions can be quite heterogeneous and diagnostic features (such as malignant osteoid) can vary from sample to sample.”

  • The paper relies on this without support.

    Fine-needle aspirates lack sufficient histological context and make tumour grade assessment difficult.

    “Fine-needle aspirates are usually inadequate for a definitive diagnosis of osteosarcoma due to the lack of sufficient histological context and the resulting difficulty to assess tumour grade, and are therefore not recommended.”

  • The paper relies on this without support.

    Most osteosarcoma patients present with high-grade lesions that have both bony and soft tissue components.

    “Most patients present with high-grade lesions that have both bony and soft tissue components, making the presence or absence of metastasis the primary risk-stratifying feature at diagnosis.”

  • The paper relies on this without support.

    Combination chemotherapy and complete surgical resection are essential for cure in osteosarcoma.

    “Combination chemotherapy and complete surgical resection are essential for cure.”

  • The paper relies on this without support.

    Osteosarcoma is radio-resistant.

    “Although osteosarcoma is regarded as a radio-resistant disease, radiotherapy as local control may be considered if resection of a primary tumour is not possible or anticipated to lead to unacceptable morbidities such as in pelvic, trunk or craniofacial primary sites of disease 104 .”

  • The paper relies on this without support.

    Outcomes for osteosarcoma have hardly improved in the past decades.

    “However, outcomes have hardly improved in the past decades, and the intensive chemotherapy regimens used are associated with important acute and long-term toxic effects and considerable impact on quality of life.”

  • The paper relies on this without support.

    Data on lower-grade osteosarcoma lesion management remain sparse.

    “Data on lower-grade lesion management remain sparse; however, most clinicians agree that grade 1 localized parosteal tumours can be treated surgically.”

  • The paper relies on this without support.

    The general principle of treating osteosarcoma subvariants is based on their grade.

    “The general principle of treating subvariants in osteosarcoma is based on their grade.”

  • The paper relies on this without support.

    Immune cell infiltration occurs in osteosarcoma.

    “based on the immune cell infiltration known to occur in osteosarcoma”

  • The paper relies on this without support.

    Data from new agents are strictly controlled by trial sponsors, preventing their application to increase understanding of the disease.

    “In addition, because these are new agents, the data is strictly controlled by trial sponsors, which prevents their application to increase understanding of the disease.”
12 of 12

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • REGOBONE median PFS conflicts with four-month PFS

    Major

    Table 2 labels the REGOBONE median PFS values as 16.4 and 4.1 months, yet gives four-month PFS values of 46% and 0%, respectively. A median time above four months is incompatible with fewer than half the patients remaining progression-free at four months.

  • Lenvatinib response percentage is rounded incorrectly

    Minor

    Two responses among 26 patients equal 7.69%, which rounds to 8%, not the reported 7%.

    Reported 7 · recomputed 7.692308

  • Reported four-month PFS range does not cover Table 2

    Minor

    The text gives a range of 35-70%, but Table 2 reports 29% for lenvatinib and 71% for cabozantinib.

  • Response-rate summary excludes the apatinib result

    Minor

    The statement that objective response rates were 10-15% conflicts with Table 2, which reports 43% for apatinib among the agents under discussion.

  • Clinical outlook reverses the reported PFS benefit

    Minor

    The outlook says MTKIs reduced progression-free survival, whereas the trial summary reports substantially higher four-month PFS with regorafenib than in its control arms. The stated direction of benefit is reversed.

  • Sorafenib response percentage is rounded incorrectly

    Minor

    Three responses among 35 patients equal 8.57%, which rounds to 9%, not the reported 8%.

    Reported 8 · recomputed 8.571429

6 of 6

Cites

Flagged first, then by citations

Research works printed but not linked: 5

  1. Czerniak, B. Dorfman and Czerniak’s Bone Tumors E-Book (Elsevier Health Sciences, 2015).
  2. Bénédicte Brounais, L.-R. & Frédéric, L. In Bone Cancer 221–239, Ch. 18 (Academic Press, 2022).
  3. Endo-Munoz, L., Evdokiou, A. & Saunders, N. A. The role of osteoclasts and tumour-associated macrophages in osteosarcoma metastasis. Biochim. Biophys. Acta 1826, 434–442 (2012).
  4. Meyers, P. A. et al. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival — a report from the Children’s Oncology Group. J. Clin. Oncol. 26, 633–638 (2008). · DOI · Paper page
  5. Wang, Z. Q., Liang, J., Schellander, K., Wagner, E. F. & Grigoriadis, A. E. c-fos-induced osteosarcoma formation in transgenic mice: cooperativity with c-jun and the role of endogenous c-fos. Cancer Res. 55, 6244–6251 (1995).

Cited by

Sorted by citations

Related

Authors
Beird, H. C., Bielack, S. S., Flanagan, A. M., Gill, J., Heymann, D., Janeway, K. A., Livingston, J. A., Roberts, R. D., Strauss, S. J., & Gorlick, R.
Affiliations
  • The University of Texas MD Anderson Cancer Center (US)
  • Olgahospital (DE)
  • University College London (GB)
  • Centre National de la Recherche Scientifique (FR)
  • Harvard University (US)
  • Nationwide Children's Hospital (US)
  • University College London Hospitals NHS Foundation Trust (GB)
ORCID
Venue
Nature Reviews Disease Primers
Publisher
Springer Science and Business Media LLC
Published
2022-12-08
Volume
8
Issue
1
Pages
77-77
ISSN
2056-676X (ISSN-L)
DOI
10.1038/s41572-022-00409-y
OpenAlex
W4313366903
Semantic Scholar
a45c4839de5d7b9e2366faa7f8f0cee9e842f5ac
Cited by
660
References
218
Citations by year
2026: 203 · 2025: 220 · 2024: 174 · 2023: 63
FWCI
19.81
Type
journal article
Language
en
Update notices
correction (2022-12-30)
Open access
Licence
Locations
  • Nature Reviews Disease Primers (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, public-domain)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • Cancer Research UK
  • National Institute for Health and Care Research
  • Agence Nationale de la Recherche (ANR-10-SATT-0008)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Sarcoma Diagnosis and Treatment
  • Health Sciences › Medicine › Rheumatology › Bone Tumor Diagnosis and Treatments
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac tumors and thrombi
Keywords
osteosarcoma, primary bone malignancy, incidence, pathogenesis, bone formation, metastasis, lung metastasis, radiographic diagnosis, bone biopsy, multidisciplinary management, late effects, quality of life
MeSH terms
Bone Neoplasms, Child, Humans, Quality of Life, Osteosarcoma

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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